Co-expression of cancer driver genes: IDH-wildtype glioblastoma-derived tumorspheres

Seon Jin Yoon, Hye Young Son, Jin Kyoung Shim, Ju Hyung Moon, Eui Hyun Kim, Jong Hee Chang, Wan Yee Teo, Se Hoon Kim, Sahng Wook Park, Yong Min Huh, Seok Gu Kang

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Driver genes of GBM may be crucial for the onset of isocitrate dehydrogenase (IDH)-wildtype (WT) glioblastoma (GBM). However, it is still unknown whether the genes are expressed in the identical cluster of cells. Here, we have examined the gene expression patterns of GBM tissues and patient-derived tumorspheres (TSs) and aimed to find a progression-related gene. Methods: We retrospectively collected primary IDH-WT GBM tissue samples (n = 58) and tumor-free cortical tissue samples (control, n = 20). TSs are isolated from the IDH-WT GBM tissue with B27 neurobasal medium. Associations among the driver genes were explored in the bulk tissue, bulk cell, and a single cell RNAsequencing techniques (scRNAseq) considering the alteration status of TP53, PTEN, EGFR, and TERT promoter as well as MGMT promoter methylation. Transcriptomic perturbation by temozolomide (TMZ) was examined in the two TSs. Results: We comprehensively compared the gene expression of the known driver genes as well as MGMT, PTPRZ1, or IDH1. Bulk RNAseq databases of the primary GBM tissue revealed a significant association between TERT and TP53 (p < 0.001, R = 0.28) and its association increased in the recurrent tumor (p < 0.001, R = 0.86). TSs reflected the tissue-level patterns of association between the two genes (p < 0.01, R = 0.59, n = 20). A scRNAseq data of a TS revealed the TERT and TP53 expressing cells are in a same single cell cluster. The driver-enriched cluster dominantly expressed the glioma-associated long noncoding RNAs. Most of the driver-associated genes were downregulated after TMZ except IGFBP5. Conclusions: GBM tissue level expression patterns of EGFR, TERT, PTEN, IDH1, PTPRZ1, and MGMT are observed in the GBM TSs. The driver gene-associated cluster of the GBM single cells were enriched with the glioma-associated long noncoding RNAs.

Original languageEnglish
Article number482
JournalJournal of translational medicine
Volume18
Issue number1
DOIs
Publication statusPublished - 2020 Dec

Bibliographical note

Funding Information:
This work was supported by the grants to S-GK from the National Research Foundation (NRF) funded by the Ministry of Science & ICT (MSIT) of Korea (NRF-2019R1A2C3004155), the Bio & Medical Technology Development Program of NRF by MSIT of Korea (NRF-2020M3E5E2037960), "Dongwha" Faculty Research Assistance Program of Yonsei University College of Medicine (6-2015-0171), and by the grants to Y-MH from the NRF funded by the Ministry of Science, ICT and Future Planning of Korea (NRF-2017M3A9G5083322, NRF-2015M3A9D7029878).

Funding Information:
We thank Dr. Lang (Department of Neurosurgery, The University of Texas, M. D. Anderson Cancer Center, Texas, USA) for providing patient-derived, GBM tumorsphere-forming GSC11 cells.

Publisher Copyright:
© 2020, The Author(s).

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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